Drug-Eluting Stents Versus Bare Metal Stents in Percutaneous Coronary Interventions (A Meta-Analysis)

Drug-Eluting Stents Versus Bare Metal Stents in Percutaneous Coronary Interventions (A Meta-Analysis) Ciro Indolfi,

MD,

Maria Pavia,

MD, MPH,

and Italo F. Angelillo,

DDS, MPH

This meta-analysis combined the results of randomized clinical trials to compare the efficacy of drug-eluting stents with that of bare metal stents in percutaneous coronary interventions to ascertain which revascularization strategy is most safe and effective. The literature identified 13 published studies, and 8 were included in the main metaanalysis, thus allowing a meta-analysis on 3,860 patients for the effect on all major adverse clinical events (MACEs) combined and for target vessel revascularization. Metaanalyses were performed for combined MACEs, patient MACEs, and thrombosis. Regression meta-analyses were performed to examine the effect of certain variables on the efficacy of drug-eluting stents compared with bare metal stents. Meta-analysis of all trials showed that drug-eluting

stents produced significant decreases in the need for percutaneous revascularization (relative risk [RR] 0.30, 95% confidence interval [CI] 0.22 to 0.40) and coronary artery bypass grafting (RR 0.54, 95% CI 0.32 to 0.89). Drugeluting stents significantly decreased all MACEs combined (RR 0.40, 95% CI 0.33 to 0.49) but were not associated with an increased risk of stent thrombosis or death. These results were confirmed at analysis as stratified by type of eluting stent, because the need for percutaneous revascularization was significantly lower for sirolimus-eluting stents (RR 0.23, 95% CI 0.15 to 0.35) and paclitaxel-eluting stents (RR 0.39, 95% CIl 0.29 to 0.53). 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:1146 –1152)

he development of drug-eluting stents (DESs), which allows controlled release of a drug directly T to the injured endothelium, may be associated with

treatment of patients who had coronary artery disease were identified by MEDLINE from January 2002 to December 2004. Further articles of potential relevance were identified by reviewing all references in the articles identified during electronic searches; in addition, to ensure that the list of studies included was as complete as possible, a manual search was conducted of the most relevant journals that cover the fields of coronary artery disease and clinical trials. The present meta-analysis is limited to randomized controlled trials published in English that included data as primary or secondary end points on major adverse clinical events (MACEs) in human subjects who underwent experimental or control treatment. If the same patients or subgroups of patients were evaluated in ⬎1 trial, only the largest dataset or that with the most relevant data or the longer follow-up was included. Odds ratio estimates of relative risk (RR) and associated 95% confidence intervals (CIs) that estimated the efficacy of DESs in decreasing MACEs for use in meta-analysis were calculated from the data presented in each report. Each report that met the inclusion criteria excluded the names and affiliations of the investigators and journal titles, and the following data were extracted: study characteristics (year of publication, location, design, and length of follow-up), patients’ characteristics (age, number of subjects enrolled in each group, percentage of patients who had diabetes in each study, mean target vessel diameter, mean lesion length, and percentage of C lesions), therapy (drug type, concentration, and mode of delivery; mean stent length; and ratio of stent length to lesion length), effect measurements as the number of MACEs (death, myocardial infarction, coronary artery bypass grafting, and target vessel or target lesion revascularization); and rate of

lower rates of restenosis compared with bare metal stents (BMSs); 2 DESs with sirolimus and paclitaxel were recently approved for clinical use by the United States Food and Drug Administration. Several randomized trials have compared BMSs with DESs for treatment of patients who have coronary artery disease and have generated enormous expectations and clinical demands for DESs, although most trials have been small. To evaluate the overall effects of DESs versus BMSs in the treatment of patients who have coronary artery disease, their effects must be accurately quantified. Meta-analyses are studies that pool data from several studies, thereby substantially enhancing the overall number of cases evaluated. This approach allows researchers to detect effects that have been overlooked in single studies because of a relatively small sample and insufficient statistical power. Therefore, this study was performed to provide an updated metaanalysis of the available clinical results of randomized trials of the DES versus the BMS.

METHODS Publications of potential relevance to our study for evaluating the efficacy of sirolimus- or paclitaxeleluting stents compared with that of BMSs for the From the Divisions of Cardiology and Hygiene, Medical School, University “Magna Græcia”, Catanzaro, Italy. Manuscript received September 17, 2004; revised manuscript received and accepted January 6, 2005. Address for reprints: Italo F. Angelillo, DDS, MPH, Division of Hygiene, Medical School, University “Magna Græcia” of Catanzaro, Via Tommaso Campanella, 88100 Catanzaro, Italy. E-mail: [email protected].

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©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 May 15, 2005

0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2005.01.040

TABLE 1 Summary of Studies on the Efficacy of Drug-eluting Stents

CORONARY ARTERY DISEASE/META-ANALYSIS ON DRUG-ELUTING STENT EFFICACY

No. of Patients in E/C

Diabetics (%)

Vessel Diameter (mean)

Lesion Length (mean)

12

120/118 30/30 59/58 58/58 129/132 131/131 533/525 175/177 662/652 37/38 39/38 39/38 37/38 533/525

19 18 20 20 13.5 15.6 26 23 24.2 15.8 12.6 15.4 10.5 26.4

2.62 2.96 2.92 2.92 2.8 2.7 2.8 2.55 2.75 3.01 2.94 2.96 2.97 2.8

9.58 11.3 10.9 10.9 10.6 10.5 14.4 15 13.4 11.8 10.7 10.5 11 14.4

S P

9 12

50/50 639/633

24 24.2

2.63 2.75

13.6 13.4

P S

9 8

524/519 129/128

28.7 24.9

2.81 2.2

11.3 11.8

Type of Drug

Follow-up (mo)

S P P (3.1 ␮g) P (1.3 ␮g) P (SR) P (MR) S S P P (0.2 ␮g) P (0.7 ␮g) P (1.4 ␮g) P (2.7 ␮g) S

12 12 6

Study RAVEL6 TAXUS I7 ASPECT8* TAXUS II9 SIRIUS10 E-SIRIUS11 TAXUS IV12 ELUTES13*

SIRIUS at 12 months14 C-SIRIUS15 TAXUS IV at 12 months16 DELIVER17* SMART18

12 9 9 9 12

Stent Length (mean)

Stent/ Lesion Ratio

Thrombosis by E/C

All

Death

MI

0 — 1 1 — — 23 — — — — — — 23.3

— — — — — — 21.4 22.6 21.8 — — — — 21.4

— — — — — — 1.49 1.51 1.63 — — — — 1.49

0/0 0/0 3/0 1/0 —/— —/— 2/4 2/0 4/5 0/1 0/1 0/1 1/1 2/4

7/34 1/3 4/3 4/3 14/29 13/28 38/99 14/40 56/98 2/6 3/6 4/6 4/6 44/117

2/2 0/0 0/0 1/0 0/2 0/0 5/3 2/1 9/7 0/0 0/0 0/0 1/0 7/4

4/5 0/0 2/1 1/1 3/7 5/7 15/17 8/4 23/24 0/0 1/0 0/0 1/0 16/18

0/1 0/1 0/0 0/0 4/1 2/2 3/8 0/3 7/22 0/1 1/1 0/1 0/1 5/9

59 —

23.8 21.8

1.75 1.63

1/1 4/5

2/9 69/127

0/0 9/8

1/2 25/30

1/0 11/25

2/9 35/88

19.8 15.9

1.75 1.58

—/— 1/4

—/— 0/2

—/— 2/10

—/— 0/2

—/— 9/25

C Lesions (%)

6.05 4.3

MACEs by E/C

62/75 12/40

CABG

TVR 0/27 1/3 2/2 2/2 10/21 7/25 20/83 7/37 24/59 2/5 1/5 4/5 2/5 23/101

*Studies that included nonpolymer-eluting stents. ASPECT ⫽ Asian Paclitaxel Eluting Stent Clinical Trial; CABG ⫽ coronary artery bypass grafting; C-SIRIUS ⫽ Canadian SIROlIMUS-coated Bx velocity balloon expandable stent; DELIVER ⫽ The Rx Achieve drug-eluting stent system; E/C ⫽ experimental/control groups; E-SIRIUS ⫽ European SIRIUS; ELUTES ⫽ European evaLUation of pacliTaxel Eluting Stent; MI ⫽ myocardial infarction; MR ⫽ moderate release; P ⫽ paclitaxel; RAVEL ⫽ Randomized double-blind study with the sirolimus-eluting Bx VELocity balloon expandable stent; S ⫽ sirolimus; SMART ⫽ Sirolimus eluting stent in the prevention of restenosis in sMall coronary ARTeries; SR ⫽ slow release; TAXUS ⫽ Treatment of de novo coronary disease using a single pAclitaXel elUting Stent; TVR ⫽ target vessel revascularization.

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0.33–0.49 0.58–2.10 0.57–1.09 0.32–0.89 0.22–0.40 0.30–1.63 0.40 1.11 0.79 0.54 0.30 0.70 3,860 3,438 3,800 3,860 3,860 3,039 9 6 8 9 9 5 8 6 7 8 8 5 0.41–0.65 0.28–2.80 0.48–1.17 0.27–1.89 0.29–0.53 — 0.52 0.89 0.75 0.71 0.39 — 1,855 1,533 1,795 1,855 1,855 — 4 2 3 4 4 — 3 2 2 3 3 — 0.26–0.42 0.52–3.18 0.40–1.53 0.20–1.19 0.15–0.35 0.21–1.94 0.33 1.29 0.79 0.49 0.23 0.63 2,005 1,905 2,005 2,005 2,005 1,767 Abbreviations as in Table 1.

5 4 5 5 5 4 5 4 5 5 5 4

No. of Patients No. of Comparisons 95% CI No. of Studies

No. of Comparisons

No. of Patients

Overall RR

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All MACEs Death MI CABG TVR Thrombosis

95% CI No. of Patients

Overall RR

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No. of Studies

Paclitaxel Only

Overall RR

95% CI

No. of Studies

No. of Comparisons

All

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Sirolimus Only

thrombosis in experimental and control groups. When studies had ⬎2 arms (to compare different administrations, schedules, or dosages), studies were split into subtrials and the control group was used for each subtrial. Two independent observers made a quality assessment of the study protocol and the data analysis and presentation of the articles using the method described by Chalmers et al.1 The readers discussed their evaluation and any disagreement was resolved through discussion and re-reading. The scale of Chalmers et al1 assigns a weighting factor to each item according to whether it has been addressed completely (full score), partly (half score), or not at all (no score). If an item in the protocol was not applicable, the number of possible points was decreased. The final score of each report was calculated as the total number of points scored divided by the total number of points believed applicable to that report, and 2 subscores concerning quality of study protocol and data analysis and presentation were calculated, yielding a range from 0 to a full score of 1. Several meta-analyses were performed for all MACEs combined (death, myocardial infarction, coronary artery bypass grafting, and target vessel or target lesion revascularization), for each MACE, and for thrombosis inclusive of all studies that examined the

TABLE 2 Summary of Results of Meta-analyses on the Efficacy of Drug-eluting Stents

FIGURE 1. Meta-analysis of risk ratios by random effect model of trials for the effect of DESs on all MACEs combined and on stent thrombosis. Abbreviation as in Table 1.

component of variance. The between-studies variance was estimated by an iterative procedure that used an estimate that was based on a restricted maximum likelihood method.4 All analyses were performed with STATA 8.1.5

RESULTS

FIGURE 2. Meta-analysis of risk ratios by random effect model of trials for the effect of DESs on the need for target vessel revascularization (TVR) and coronary artery bypass grafting (CABG). Other abbreviations as in Table 1.

efficacy of DESs and then of only studies that used a particular DES (sirolimus or paclitaxel). Data were extracted in a contingency table format. The random effect model described by DerSimonian and Laird2 was used to combine the collected values. This model calculates a weighted average of the relative risks by incorporating within-study and between-study variations. The Mantel-Haenszel method (fixed effect model)3 was also used to assess the effect of model assumptions on our conclusions. Compared with the fixed effect model, which considers only the within-study variation, the random effect model generally provides a similar estimate of the RR but a wider CI if heterogeneity is present. Univariate and multivariate regression meta-analyses were performed to examine the effect of certain variables, such as type of drug used in eluting stents, number of patients who had diabetes expressed as percentage of patients enrolled in each study, baseline mean lesion length, baseline mean vessel diameter, number of more severe lesions expressed as percentage of C lesions, mean stent length, and ratio of stent length to lesion length on the efficacy of DESs compared with BMSs. The random effects regression model related the treatment effect to the covariates, assuming a normal distribution for the residual errors with a within-study and an additive between-studies

Fifty-four publications were identified as potentially eligible for inclusion; of these, 13 met our inclusion criteria (Table 1) and were published from 2002 to 2004, and 2 reported results at 12 months of previous studies followed at 9 months.6 –18 The 2 original studies (SIRolImUS-coated Bx velocity balloon expandable stent [SIRIUS] and Treatment of de novo coronary disease using a single pAclitaXel elUting Stent [TAXUS IV]) that reported results at 9 months are presented in Table 1, but only results at 12 months were included in the meta-analysis. Sirolimuseluting stents were used in 6 studies, polymer-eluting paclitaxel stents in 4, and nonpolymer paclitaxel-eluting stents in the remaining 3. Because these latter studies used a stent that was not approved by the United States Food and Drug Administration and were significantly different from the other studies, they were excluded from the main meta-analysis and pooled into a separate meta-analysis. Therefore, 8 studies were available for the main meta-analysis. In most trials, only 2 arms were involved, and in all studies the control therapy consisted of BMSs. Data on percutaneous revascularization involved target vessels in 3 studies,9,12,16 target lesions in 8 studies,8,10,11,13–15,17,18 and target vessels and target lesions in 2 studies.6,7 Subjects’ mean age range was 60 to 66 years. There were 30 to 662 patients in treatment groups and 30 to 652 in control groups; the smallest proportion of enrolled patients who had diabetes was 13.5% and the highest was 28.7%; mean vessel diameter was 2.2 to 3.01 mm, and mean lesion length was 9.58 to 14.4 mm. Mean quality scores were 0.54 to 0.87 (median 0.78) for single studies, 0.62 to 0.94 for study protocol, and 0.41 to 0.75 for data analysis and presentation. All studies received full credit for describing the daily amount and timing of therapeutic regimens, blinding to treatment of patients and observers, and test of validity of randomization (100%) and the most credit for describing inclusion and exclusion criteria for patient selection, physical appearance of treatment and placebo, and methods used to evaluate success of blinding (92.3%). With regard to data analysis and presentation, all studies reported a measurement of variance but not all CIs (46.1%), whereas most trials reported p values (69.2%), and 30.8% also reported test statistics; overall quality of statistical analysis was rated as full (53.8%) or partial (46.2%). MACEs occurred less frequently in the DES group in all 9 comparisons, 8 of which showed statistically significant differences (88.9%; Figure 1). All studies combined showed a statistically significant decrease in MACEs with the use of DESs (RR 0.40, 95% CI 0.33 to 0.49), with a pooled estimate of 60% for DES efficacy (Figure 1 and Table 2). A decreased need for percuta-

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TABLE 3 Results From Univariate and Multivariate Regression Meta-analyses Relating Several Variables to Effect Size Estimates of Trials Evaluating the Efficacy of Drug-eluting Stents in Preventing Major Adverse Clinical Events and Target Vessel Revascularization Univariate Variables All MACEs combined Type of drug (sirolimus ⫽ 0, paclitaxel ⫽ 1) % Diabetics (continuous) Mean lesion length (continuous) Mean vessel diameter (continuous) % C-lesions (continuous) Mean stent length (continuous) Stent length/lesion length (continuous) TVR Type of drug (sirolimus ⫽ 0, paclitaxel ⫽ 1) % Diabetics (continuous) Mean lesion length (continuous) Mean vessel diameter (continuous) % C lesions (continuous) Mean stent length (continuous) Stent length/lesion length (continuous)

Multivariate

Regression Coefficient

Z Score

p Value

Regression Coefficient

Z Score

p Value

⫹0.449 ⫺0.009 ⫹0.026 ⫹0.787 ⫹0.008 ⫹0.046 ⫹1.918

2.67 ⫺0.35 0.40 1.35 0.73 0.74 1.39

0.008 0.73 0.69 0.18 0.46 0.46 0.16

⫹0.519 ⫺0.007 ⫹0.092 ⫹0.025 NI NI NI

2.54 ⫺0.18 0.89 0.04 NI NI NI

0.011 0.86 0.37 0.97 NI NI NI

⫹0.482 ⫺0.031 ⫺0.128 ⫹0.035 ⫺0.012 ⫺0.05 ⫹3.234

2.11 ⫺1.0 ⫺1.55 0.05 ⫺0.83 ⫺0.63 1.81

0.035 0.32 0.12 0.96 0.41 0.53 0.07

⫹0.490 ⫹0.031 ⫺0.111 ⫺0.257 NI NI NI

1.52 0.56 ⫺0.62 ⫺0.29 NI NI NI

0.13 0.58 0.54 0.77 NI NI NI

NI ⫽ not included; other abbreviations as in Table 1.

neous revascularization in the DES group was found in all 9 comparisons (Figure 2), and this beneficial effect was statistically significant in 8 comparisons. Meta-analysis of all trials showed that DESs produced a significant decrease in the need for percutaneous revascularization (RR 0.30, 95% CI 0.22 to 0.40), with a DES efficacy of 70% (Figure 2 and Table 2). A decrease in coronary artery bypass grafting in the DES group was ascertained by 6 of 9 comparisons (Figure 2); all but 1 were statistically nonsignificant, whereas meta-analysis of all trials showed a significant decrease in coronary artery bypass grafting with a DES efficacy of 46% (RR 0.54, 95% CI 0.32 to 0.89). For all other investigated events (death, myocardial infarction, and thrombosis), no significant difference was found in the performance of DESs compared with controls, although a RR in favor of patients who received DESs was ascertained for myocardial infarction (RR 0.79, 95% CI 0.57 to 1.09) and thrombosis (RR 0.70, 95% CI 0.30 to 1.63; Figure 1), whereas the opposite occurred for death (RR 1.11, 95% CI 0.58 to 2.10; Table 2). Results of meta-analyses as stratified by type of eluting drug showed a very consistent pattern within the analyses and with analysis of all studies. All MACEs and need for percutaneous revascularization were significantly decreased with sirolimus- and paclitaxel-eluting stents, although the protective effect appeared to be more pronounced for the sirolimuseluting stent (RR 0.33, 95% CI 0.26 to 0.42 for MACEs; RR 0.23, 95% CI 0.15 to 0.35 for target vessel revascularization) compared with the paclitaxeleluting stent (RR 0.52, 95% CI 0.41 to 0.65 for MACEs; RR 0.39, 95% CI 0.29 to 0.53 for target vessel revascularization; Table 2). For death, myocardial infarction, and thrombosis, results of stratified analysis were very similar to those of the overall analysis (Table 2). 1150 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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Meta-analyses of studies on nonpolymer paclitaxel-eluting stents showed no significant benefit of DESs compared with BMSs in decreasing MACEs (RR 0.79, 95% CI 0.60 to 1.03), death (RR 3.04, 95% CI 0.32 to 28.69), myocardial infarction (RR 1.94, 95% CI 0.48 to 7.9), coronary artery bypass grafting (RR 0.48, 95% CI 0.10 to 2.14), target vessel revascularization (RR 0.57, 95% CI 0.29 to 1.11), and thrombosis (RR 1.01, 95% CI 0.29 to 3.49). No significant heterogeneity was detected among the studies that were included in the meta-analysis that evaluated the effect of DESs on all MACEs combined or in meta-analyses that were stratified by each clinical event and by each eluting drug (sirolimus or paclitaxel). Univariate and multivariate regression metaanalyses showed that the efficacy of sirolimus was significantly superior to paclitaxel in decreasing all MACEs combined, whereas all other factors considered did not significantly influence efficacy. With regard to efficacy of DESs in decreasing the need for target vessel revascularization, none of the variables tested in the multivariate regression meta-analysis seemed to significantly influence our results, although sirolimus appeared to be superior to paclitaxel in the univariate regression meta-analysis (Table 3). Univariate and multivariate regression meta-analyses were also performed to identify variables that affected the efficacy of DESs compared with BMSs in the prevention of coronary artery bypass grafting, but none of the variables tested seemed to significantly influence the results (data not shown).

DISCUSSION The present meta-analysis indicates that DESs are better than BMSs in decreasing the need for additional procedures of revascularization after percutaneous coronary interventions. These beneficial effects were not associated with a decrease or increase in other MAY 15, 2005

adverse cardiac events (i.e., death, myocardial infarction, and stent thrombosis). Further, these favorable results were sustained during long-term follow-up. In addition, DESs were associated with better clinical outcomes than were BMSs, irrespective of the type of drug used (sirolimus or paclitaxel). The production of an overall estimate of the efficacy of DESs is challenging because the patient studies differ according to drug type, dose, and mode of delivery; length of follow-up; baseline characteristics of the study population; outcomes measured; and other methodologic aspects. Because the studies that involved a nonpolymer-eluting stent differed substantially from the other trials, we believed they might represent a source of heterogeneity and excluded them from the main analysis. Therefore, we performed meta-analyses that were stratified by each outcome of interest and by type of drug (sirolimus or paclitaxel) used. Statistical heterogeneity can also be caused by defects of methodologic quality of single trials, and there is debate concerning the use of quality scores as an inclusion criterion in meta-analysis. Because no substantial variability in quality scores was detected, we excluded quality as a potential source of heterogeneity. Stratified analysis and regression meta-analysis allowed us to hypothesize a better performance of sirolimus in decreasing all MACEs and a need for target vessel revascularization. In none of the studies were the 2 DESs compared, so these results should be interpreted with extreme caution. However, these results should be confirmed by ongoing trials that compare the 2 DESs head to head. Our literature search identified 13 studies that met the inclusion criteria and the largest trial enrolled 1,314 patients, whereas our meta-analysis allowed us to summarize information on 3,860 patients for all MACEs and need for target vessel revascularization. Moreover, most trials were designed to detect differences in luminal diameter as measured by quantitative angiography, whereas our meta-analysis permitted a study of a sufficient number of clinical events in experimental and control groups. Although BMS deployment has been shown to decrease the rate of restenosis compared with balloon angioplasty,19,20 in-stent restenosis remains a significant and increasing clinical problem, with increased BMS implantation in interventional cardiology. The mechanism of restenosis after stenting has been demonstrated by Hoffmann et al,21 who found that late luminal area strongly correlates with tissue growth in stented segments but only weakly with remodeling. Therefore, with the use of the intravascular ultrasound analysis, it has been demonstrated that long-term stent recoil is minimal and late luminal loss and in-stent restenosis are mainly caused by neointimal tissue proliferation.22 Further, because stents have been shown to achieve larger acute luminal dimensions (compared with balloon angioplasty), stents appear to withstand arterial remodeling (the dominant mechanism of late luminal loss in nonstented lesions), and late luminal loss is proportionate to acute luminal gain.22 Thus, the major limitation to stent implantation is the initiation

of smooth muscle cell proliferation within and adjacent to the stent. Two recent meta-analyses of published trials on the same topic,23,24 although the approach was somewhat different, reported similar conclusions and emphasized the need for results of longer follow-up periods and for subgroups of patients (who have diabetes and so forth), and this corroborates the results of our study, which could include results for longer periods of follow-up and for more recently published trials. Because this meta-analysis definitely demonstrated the superiority of DESs to BMSs, future studies that assess the efficacy of a new DES should no longer be tested against placebo. Perhaps new trials of noninferiority (or of superiority) of 1 of the 2 available DESs should be planned to evaluate new DESs. 1. Chalmers TC, Smith H Jr, Blackburn B, Silverman B, Schroeder B, Reitman

D, Ambroz A. A method for assessing the quality of a randomized control trial. Control Clin Trials 1981;2:31– 49. 2. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188. 3. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719 –748. 4. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis. A comparison of methods. Stat Med 1999;18:2693–2708. 5. STATA Reference Manual. Release 8.1. College Station, TX: STATA, 2003. 6. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, et al. Study with the sirolimuscoated bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimuseluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780. 7. Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerckens U, Russell ME. TAXUS I: six-and twelve-month results from a randomized, doubleblind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38 – 42. 8. Park S-J, Shim WH, Ho DS, Raizner AE, Park S-W, Hong M-K, Lee CW, Choi D, Jang Y, Lam R, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med 2003;348:1537–1545. 9. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108:788 –794. 10. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 11. Schofer J, Schluter M, Gershlick AH, Wijns W, Garcia E, Schampaert E, Breithardt G. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS). Lancet 2003;362:1093–1099. 12. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shoughnessy C, Tift Mann J, Turco M, Caputo R, Bergin P, Greenberg J, et al, for the TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231. 13. Gershlick A, De Scheerder I, Chevalier B, Stephens-Lloyd A, Camenzind E, Vrints C, Reifart N, Missault L, Goy JJ, Brinker JA, et al. Inhibition of restenosis with a paclitaxel-eluting, polymer-free coronary stent: the European Evaluation of Paclitaxel Eluting Stent (ELUTES) trial. Circulation 2004;109: 487– 493. 14. Holmes DR Jr, Leon MB, Moses JW, Popma JJ, Cutlip D, Fitzgerald PJ, Brown C, Fischell T, Wong SC, Midei M, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation 2004;109:634 – 640. 15. Schampaert E, Cohen EA, Schluter M, Reeves F, Traboulsi M, Title LN, Kuntz RE, Popma JJ. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110 –1115. 16. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Tift Mann J, Turco M, Caputo R, Bergin P, Greenberg J, et al, for the TAXUS-IV Investigators. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation 2004;109: 1942–1947.

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17. Lansky AJ, Costa RA, Mintz GS, Tsuchiya Y, Midei M, Cox DA,

O’Shaughnessy C, Applegate RA, Cannon LA, Mooney M, et al. Non-polymerbased paclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial. Circulation 2004;109:1948 –1954. 18. Ardissino D, Cavallini C, Bramucci E, Indolfi C, Marzocchi A, Manari A, Angeloni G, Carosio G, Bonizzoni E, Colusso S, et al, for the SES-SMART Investigators. Sirolimus-eluting vs uncoated stents for prevention of restenosis in small coronary arteries. JAMA 2004;292:2727–2734. 19. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, for the Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331: 489 – 495. 20. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, et al. A randomized comparison of

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